PROJECT ABSTRACT Per- and polyfluoroalkyl substances (PFASs) can be detected in the serum of 98% of Americans and have been linked to several severe health effects, including cancer and inflammatory diseases. Many of these health effects are linked to dysregulation of innate immune function, but how PFASs impact innate immunology is widely unknown. Preliminary data show that PFAS exposure suppresses innate immune function in vitro and in vivo. Further, PFAS exposure is associated with thyroid disease, and normal thyroid hormone levels are essential for innate immune function. Therefore, the central hypothesis is that PFAS-induced immunotoxicity is mediated by decreased thyroid hormone signaling. This hypothesis will be tested for multiple structurally diverse PFASs in both human innate immune cell lines and a hypothyroid zebrafish model. Aim 1 will determine if PFAS-induced suppression of natural killer (NK) cell function requires thyroid hormone signaling in vitro. Aim 2 will determine if PFAS-induced suppression of phagocyte cell function requires thyroid hormone signaling in vivo and in vitro. This work will begin to fill the knowledge gap surrounding PFAS-induced toxicity, specifically as it relates to their immunotoxicity and their potential mechanisms of action. Successful completion of this project will inform hazard identification and risk assessment processes and may lead to improved regulation of PFASs in the environment.